Best of heart failure

17 been hospitalized with heart failure in the past 12 months. Ivabradine significantly reduced the relative risk of hospital- ization for worsening HF or CV death (RRR 18%, p < 0.0001); the significance is driven mostly by a reduction of rehospitalization. HFNEF describes a heterogeneous pool of patients that make about 50% of HF patients with a unique set of patho- physiologic mechanisms. These patients are typically older with hypertension, obesity, renal failure, anemia, and atrial fibrillation and are more likely to be females. There is also a high incidence of diabetes and coronary artery disease in these patients [ 7 ]. In contrast to patients with impaired left ventricular EF, HFNEF patients have non-dilated left ven- tricular cavity size, concentric instead of eccentric left ven- tricular hypertrophy, and a normal EF [ 34 ]. It is controversial whether LV systolic function is truly normal in patients with HFNEF because EF is an imprecise measure of left ventricular systolic function. However, inva- sive conductance studies suggested from pressure–volume loops that end-systolic pressure–volume relationship is steeper or normal in HFNEF suggesting a normal systolic function. On the other hand, end-diastolic pressure–volume relationship is shifted leftward and upward indicating dia- stolic dysfunction [ 35 , 36 ]. Diastolic dysfunction is not uncommon among elderly patients estimated at about 5.6%, but only 1% has HFNEF [ 37 ]. In one study, the product of left ventricular mass index and left atrial volume has the highest predictive accuracy for HFNEF [ 38 ]. In addition to ventricular stiffness, arterial stiffness has also been suggested to contribute to HFNEF, and the combined ventricular–arterial stiffness leads to an exaggerated hypertensive response after small increases in LV end-diastolic volume [ 7 ]. 24.3 ACC/AHA Classification of Congestive Heart Failure The current ACC/AHA classification for CHF [ 3 ] is comple- mentary to the New York Heart Classification (NYHC) [ 39 ] and helps define the evolution of symptoms of patients with CHF. In addition, the ACC/AHA classification focuses on the risk factors for CHF by identifying patients who have risk factors for CHF. This classification includes four stages of CHF: Stage A: Asymptomatic patients with no left ventricular dys- function but are at risk of developing CHF including patients with coronary artery disease, hypertension, dia- betes mellitus, family history of cardiomyopathy, and the metabolic syndrome. Stage A is not represented in the NYHC. Stage B : Asymptomatic patients with left ventricular dys- function. This is equivalent to Class I of the NYHC. Stage C : Symptom ventricular dysf Class II and Clas ple in the United Stage D : Symptom Class IV of the in the United Sta 24.4 Pharma Heart Fa 24.4.1 Heart Fai Fraction Dysfunct As noted above, o nisms of HFNEF is with diastolic dysf patients with HF a HFNEF. “True” H nary artery disease, strictive cardiomyo and right-sided fail mia, thyrotoxicosis carditis, or intracar Diastolic dysfun ditions including cor lar disease, age [ 4 secondary to intrace [ 42 ], and hypertrop ARB (losartan) has but did not change l Isolated diastolic identified in 11.5% ease with the use o atrial size and N-t (NT-proBNP) appe function [ 45 ]. Also, are seen with differe Recently an algo posed by the work Cardiology [ 47 ]. In toms of HF, normal with evidence of a distensibility, and d of HFNEF if one of PCWP > 12 mmHg ing, E/E ′ > 15 by ti DopplerwithaBNP mL or BNP > 200 and LVH or atrial mal pulmonary ven 24 Evidence-Based Management of the Patient with Congestive Heart Failure 457 24.4.10 Digoxin Therapy in Congestive Heart Failure Digoxin was introduced by William Withering and has been used therapeutically for more than 250 years [ 119 ]. It has been widely used in the treatment of atrial fibrillation as a rate control agent, but its utility in CHF has been debated. The Digitalis Investigation Group (DIG) [ 120 ] is a ran- domized, double-blind clinical trial that studied the effects of digoxin on mortality and hospitalization in patients with congestive heart failure. DIG showed no advantage of digoxin on mortality at 37 months follow-up. Digoxin, how- ever, reduced the rate of hospitalization for worsening heart failure. A comprehensive post hoc analysis, however, of the DIG showed that digoxin at a serum concentration of 0.5– 0.9 ng/mL did reduce mortality (29% versus 33%, adjusted hazard ratio (AHR) of 0.77) and heart failure hospitaliza- tions (23% versus 33%, AHR of 0.68) in all heart failure patients with no interaction with EF > 45% ( p = 0.834) or gender ( p = 0.917) [ 121 ]. In another substudy of the DIG trial, perceived health, quality of life measures, and the 6-min walk test were not statistically different between digoxin and placebo in patients in normal sinus rhythm at 12-month follow-up [ 122 ]. Furthermore, digoxin efficacy was not altered by renal glomerular filtration, but renal dys- function was a predictor of mortality in patients with GFR < 50 mL/min [ 123 ]. Patients on digoxin and receiving standard treatment for congestive heart failure might experience a slight reduction in EF [ 124 – 127 ], worsening maximal exercise capacity, and increased incidence of treatment failure upon withdrawal of this drug [ 125 , 127 ]. Currently, digoxin is indicated for the treatment of chronic heart failure in patients with left ventricular dysfunction and NYHC Class II–III despite optimal medical treatment with ACEI, beta blockers, and diuretics (ACC/AHA Class IIa indication). Digoxin is not indicated for the acute treatment of CHF, and serial measurements of digoxin levels are cur- rently considered unnecessary. Digoxin dose needs to be reduced when administered with amiodarone. 24.4.11 Mechanical Treatment of Stage C Heart Failure 24.4.11.1 Cardiac Resynchronization Therapy Cardiac resynchronization therapy (CRT) is indicated in patients with advanced heart failure symptoms (Class III or IV) despite optimal medical management, an EF ≤ 35%, sinus rhythm, and cardiac dyssynchrony defined as a wide QRS complex >120 ms. The outcomes of CRT system implantation in 2078 patients from a multicenter study program showed that the procedure is safe, well-tolerated, and has a high success rate [ 128 ]. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial [ 128 ], 369 patients with EF ≤ 35%, QRS duration ≥ 130 ms, and Class III–IV NYHC, despite optimal medical treatment, were random- ized to controls ( n = 182, ICD activated, CRT off) and the CRT group ( n = 187, ICD activated, CRT on). CRT improved quality of life, functional status, and exercise capacity without adversely influencing ICD function. In addition, in the InSyncIII study [ 129 ], a multicenter, pro- spective, non-randomized, 6-month trial of 422 patients with wide QRS complex and a Class III or IV heart failure, sequential CRT therapy provided a modest increase in stroke volume and improved exercise capacity but had no change in functional status or quality of life compared to a historic control from the MIRACLE trial. Furthermore, improvement in left ventricular function that occurs with CRT is more prominent in patients with nonischemic heart failure and less severe mitral insufficiency [ 130 ]. Finally, in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, the risk of the combined endpoint of death from, or hospitaliza- tion for, heart failure was reduced by 34% ( p < 0.002). In the same trial, death from any cause was reduced by 24% ( p = 0.059) in the pacemaker group co pared to the medi- cal therapy alone [ 131 ]. In this trial, the addition of a defi- brillator reduced mortality beyond that achieved with CRT therapy alone. Current guidelines recommend CRT therapy in patients with advanced heart failure symptoms and wide QRS complex who are already optimized on medical treatment with the goal to improve exercise capacity, functional sta- tus, and quality of life and to help reverse left ventricular remodeling [ 74 ]. 24.4.11.2 Implantable Cardioverter Defibrillators Sudden death is a major cause of mortality in patients with left ventricular dysfunction. Implantable cardioverter defi- brillators (ICD) are currently indicated in patients with mod- erate CHF and reduced EF < 30% on optimal medical therapy who have a reasonable expectation of survival for more than 1 year who are at least 40 days post-myocardial infarction, have nonischemic cardiomyopathy, or have had a serious arrhythmia such as ventricular fibrillation, ventricular tachy- cardia, or cardiac arrest [ 73 , 132 ]. In the Sudden Cardiac Death in Heart Failure Trial (SCD- HeFT), 2521 patients with moderate heart failure and an EF ≤ 35% were randomized to conventional therapy for CHF plus placebo, conventional therapy plus amiodarone, or conventional therapy plus ICD. Amiodarone had no 24 Evidence-Based Management of the Patient with Congestive Heart Failure